What are the approved indications, dosing regimens, administration guidelines, monitoring schedule, and management of immune‑related adverse events for durvalumab in adult solid‑tumor malignancies?

Durvalumab: Approved Indications, Dosing, Administration, and Management

Approved Indications

Durvalumab is FDA-approved for urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma (in combination with tremelimumab), biliary tract cancer, and endometrial cancer, but NOT for gastric cancer. 1, 2

Specific Approved Uses:

• Locally advanced or metastatic urothelial carcinoma following disease progression during or after platinum-based chemotherapy 1, 3
• Stage III NSCLC as consolidation therapy after concurrent chemoradiotherapy without disease progression 1
• Limited-stage SCLC as consolidation therapy after concurrent chemoradiotherapy (1,500 mg every 4 weeks for up to 24 months, demonstrating median OS of 55.9 months vs 33.4 months with placebo; HR 0.73) 4
• Hepatocellular carcinoma in combination with tremelimumab (300 mg single dose tremelimumab plus durvalumab 1,500 mg every 4 weeks, showing median OS 16.43 vs 13.77 months compared to sorafenib; HR 0.78) 4
• Endometrial cancer in combination with carboplatin and paclitaxel 1

---

Dosing Regimens

Standard Dosing:

• 1,500 mg intravenously every 4 weeks (preferred fixed-dose regimen for patients >30 kg) 4, 1
• 10 mg/kg intravenously every 2 weeks (alternative weight-based dosing) 1, 3, 5
• 20 mg/kg every 4 weeks when combined with tremelimumab 1 mg/kg every 4 weeks for 4 doses, followed by durvalumab monotherapy 4, 1

Duration of Therapy:

• Up to 12 months for most solid tumors 1, 3, 5
• Up to 24 months for limited-stage SCLC consolidation 4
• Continue until disease progression, unacceptable toxicity, or initiation of another anticancer therapy 1, 3

Pharmacokinetic Considerations:

• Steady state achieved at approximately 16 weeks 1
• Terminal half-life approximately 21 days 1
• No dose adjustments required for mild-to-moderate renal impairment (CrCl 30-89 mL/min), mild-to-moderate hepatic impairment, age (18-96 years), or body weight (31-175 kg) 1
• Effect of severe renal impairment (CrCl 15-29 mL/min) or severe hepatic impairment (bilirubin >3× ULN) is unknown 1

---

Administration Guidelines

Preparation and Infusion:

• Administer as intravenous infusion over 60 minutes 1
• Do not administer as intravenous push or bolus 1
• Inspect visually for particulate matter and discoloration; solution should be clear to opalescent, colorless to slightly yellow 1

Formulations Available:

• 500 mg/10 mL vial (50 mg/mL concentration) 1
• 120 mg/2.4 mL vial (50 mg/mL concentration) 1

Compatibility:

• Contains L-histidine, L-histidine hydrochloride monohydrate, α,α-trehalose dihydrate, Polysorbate 80, and Water for Injection 1

---

Monitoring Schedule

Baseline Assessment:

• Liver function tests (AST, ALT, bilirubin) 1
• Renal function (creatinine, estimated GFR) 1
• Thyroid function tests (TSH, free T4) 1
• For hepatocellular carcinoma patients: Esophagogastroduodenoscopy to evaluate for gastroesophageal varices before initiating therapy, particularly when combined with bevacizumab 4

During Treatment Monitoring:

• Liver enzymes and bilirubin before each cycle 1
• Thyroid function every 6-12 weeks (hypothyroidism occurs in approximately 10.9% of patients) 4
• Pulmonary symptoms assessment at each visit (pneumonitis occurs in 1.2% of patients) 4
• Dermatologic examination (pruritus and rash are common, occurring in 32.4% when combined with tremelimumab) 4

Response Assessment:

• Tumor imaging every 8-12 weeks using RECIST v1.1 criteria 3
• Median time to response is 1.41 months 3

---

Management of Immune-Related Adverse Events

General Principles:

Early recognition and prompt intervention with immune suppression is critical for managing immune-related adverse events (irAEs), which occur in up to 32.1% of patients receiving durvalumab. 4

Grade-Specific Management Algorithm:

Grade 1 irAEs:

• Continue durvalumab with close monitoring 4
• Symptomatic management as appropriate 4

Grade 2 irAEs:

• Withhold durvalumab until symptoms resolve to Grade ≤1 4, 1
• Initiate corticosteroids: prednisone 0.5-1 mg/kg/day or equivalent 4
• Resume durvalumab when symptoms improve and corticosteroid dose tapered to ≤10 mg/day prednisone equivalent 4

Grade 3 irAEs:

• Permanently discontinue durvalumab 4, 1
• Initiate high-dose corticosteroids: prednisone 1-2 mg/kg/day or equivalent (9% of patients require ≥40 mg daily) 4, 6
• Consider additional immunosuppressive agents if no improvement within 48-72 hours 4

Grade 4 irAEs:

• Permanently discontinue durvalumab immediately 4, 1
• Initiate high-dose intravenous corticosteroids: methylprednisolone 1-2 mg/kg/day 4
• Add second-line immunosuppressive agents (infliximab, mycophenolate mofetil) if refractory to corticosteroids 4

Organ-Specific Management:

Pneumonitis (1.2% incidence):

• Grade 2: Withhold durvalumab, prednisone 1 mg/kg/day, chest imaging, pulmonology consultation 4, 1
• Grade 3-4: Permanently discontinue, methylprednisolone 2 mg/kg/day IV, bronchoscopy to exclude infection 4

Hepatitis:

• Grade 2 (AST/ALT 3-5× ULN): Withhold durvalumab, prednisone 0.5-1 mg/kg/day, monitor LFTs every 3 days 4, 1
• Grade 3-4 (AST/ALT >5× ULN or bilirubin >3× ULN): Permanently discontinue, methylprednisolone 1-2 mg/kg/day IV, hepatology consultation 4, 1
• Fatal autoimmune hepatitis has been reported 3

Colitis/Diarrhea:

• Grade 2: Withhold durvalumab, prednisone 1 mg/kg/day, loperamide, hydration 4
• Grade 3-4: Permanently discontinue, methylprednisolone 1-2 mg/kg/day IV, consider infliximab 5 mg/kg if no improvement in 3-5 days 4

Endocrinopathies:

• Hypothyroidism (10.9% incidence): Continue durvalumab, initiate levothyroxine replacement, monitor TSH every 6 weeks 4, 1
• Hyperthyroidism: Withhold durvalumab for Grade 3-4, initiate beta-blockers and methimazole, endocrinology consultation 4, 1
• Adrenal insufficiency: Permanently discontinue for Grade 3-4, hydrocortisone 100 mg IV every 6-8 hours, lifelong replacement therapy 4, 1

Dermatologic Reactions:

• Pruritus and rash (32.4% with combination therapy): Topical corticosteroids, oral antihistamines, continue durvalumab unless Grade 3-4 4
• Grade 3-4: Withhold durvalumab, systemic corticosteroids, dermatology consultation 4

---

Safety Profile and Common Pitfalls

Most Common Treatment-Related Adverse Events:

• Fatigue (20.4-35%) 4, 6
• Rash and pruritus (19.5-32.4%) 4, 5
• Hypothyroidism (10.9%) 4
• Diarrhea (18.8-27.5%) 4, 7

Grade 3-4 Treatment-Related Adverse Events:

• Monotherapy: 6.8-8.2% 4, 3
• Combination with tremelimumab: 17.5% 4
• Combination with chemotherapy: 8.8% 4

Critical Safety Considerations:

For hepatocellular carcinoma patients receiving durvalumab with bevacizumab-containing regimens, mandatory esophagogastroduodenoscopy screening and management of gastroesophageal varices is required before treatment initiation due to 7% incidence of upper gastrointestinal bleeding. 4

Treatment-Related Deaths:

• Overall incidence: 1.6-2.7% 4, 3
• Fatal immune-mediated events include autoimmune hepatitis and pneumonitis 3

Immunogenicity:

• Anti-drug antibodies develop in 3.2% of patients 1
• Neutralizing antibodies in 19.2% of ADA-positive patients 1
• No clinically significant effects on pharmacokinetics or safety identified 1, 5

Common Pitfalls to Avoid:

• Do not delay corticosteroid initiation for Grade 2-4 irAEs; early intervention prevents progression 4
• Do not use durvalumab in patients with active autoimmune disease requiring systemic immunosuppression 1
• Do not restart durvalumab after Grade 3-4 irAEs except for endocrinopathies managed with replacement therapy 4, 1
• Do not use live vaccines during durvalumab treatment 1
• Do not assume PD-L1 testing is required for most indications; it is only mandatory for specific first-line urothelial carcinoma scenarios with pembrolizumab or atezolizumab monotherapy 8